Faculty Research

Anthony Quinn

Research

The question of how autoimmunity is initiated and maintained has been argued for a
considerable time; however, there is a consensus opinion that autoimmune disease is
the product of several interacting factors, with genetics and environment contributing
the greatest impact. Whether there is an environmental instigator which induces a
lymphocyte response cross-reactive with a self-molecule ("molecular mimicry"), or
whether the prime mover relates mainly to an inflammatory injury resulting from a
microbial infection are critical to our understanding of the pathogenesis of autoimmune
disease. For example, acute rheumatic fever, which represents one of the best examples
of molecular mimicry, is an autoimmune disease that is preceded by a pharyngeal infection
with group A streptococcus. Strikingly, molecules associated with streptococcus can
mimic cardiac proteins and induce heart-reactive antibodies and T cells which are
detected in the blood and hearts of patients with rheumatic heart disease. Nevertheless,
the progression from infection to autoimmunity to autoimmune disease is a rare event
such that the majority of individuals exposed to group A streptococcus - including
those that may develop autoreactive antibodies - do not develop rheumatic heart disease.
The evidence to date suggests that autoimmune responses in certain susceptible individuals
will sufficiently perturb immunological homeostasis as to create a state of dysregulation
and autoimmune disease. Our lab focuses on delineating the mechanisms that are involved
in the activation and uncontrolled expansion of pathogenic autoimmune responses by
microbial organisms. Conversely we are also engaged in studies to reveal the regulatory
responses that seem to provide protection to normal individuals.

One of the most interesting animal models of autoimmune disease is insulin-dependent
diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse. IDDM in the NOD mouse
results from a T lymphocyte-mediated destruction of the insulin-producing b cells
of the pancreas and serves as a model for human type I diabetes. Prior to the onset
of diabetes, young NOD mice develop T cell responses to the islet antigens glutamic
acid decarboxylase (GAD65) and insulin. GAD65 and insulin; 1) are targets for autoreactive
antibodies and T lymphocytes in young pre-diabetic NOD mice and humans (these responses
are used for clinical diagnosis), 2) are capable of inducing diabetogenic T lymphocytes
and overt diabetes, and 3) are the current focus of therapeutic approaches to prevent
type I diabetes in humans. By studying T lymphocyte responses to GAD65 and insulin
we hope to identify immunoregulatory mechanisms that can be used to induce specific
regulation in both the CD4+ and CD8+ T lymphocyte compartments of the anti-islet response.
We are currently investigating the activities of certain peptides that can alter the
effector function of pathogenic GAD65-specfic T lymphocytes. Furthermore, are continuing
our efforts to design and characterize peptides that can be used to induce the expansion
of regulatory/protective T lymphocytes. The combination of these approaches should
allow us to define fragments of self-molecules that can be used alone or in combination,
to modulate the autoimmune response responsible for islet cell damage and IDDM in
NOD mice. Moreover, the principles learned may provide important clues for the amelioration
of T lymphocyte-mediated autoimmune diseases, such as diabetes, myocarditis, arthritis,
and multiple sclerosis, in human as well.